Left atrial reservoir strain as a predictor of cardiac outcome in patients with heart failure: the HaFaC cohort study

Background The left atrium (LA) is a key player in the pathophysiology of systolic and diastolic heart failure (HF). Speckle tracking derived LA reservoir strain (LASr) can be used as a prognostic surrogate for elevated left ventricular filling pressure similar to NT-proBNP. The aim of the study is to investigate the correlation between LASr and NT-proBNP and its prognostic value with regards to the composite endpoint of HF hospitalization and all-cause mortality within 1 year. Methods Outpatients, sent to the echocardiography core lab because of HF, were enrolled into this study. Patients underwent a transthoracic echocardiographic examination, commercially available software was used to measure LASr. Blood samples were collected directly after the echocardiographic examination to determine NT-proBNP. Results We included 174 HF patients, 43% with reduced, 36% with mildly reduced, and 21% with preserved ejection fraction. The study population showed a strong inverse correlation between LASr and log-transformed NT-proBNP (r = − 0.75, p < 0.01). Compared to NT-proBNP, LASr predicts the endpoint with a comparable specificity (83% vs. 84%), however with a lower sensitivity (70% vs. 61%). Conclusion LASr is inversely correlated with NT-proBNP and a good echocardiographic predictor for the composite endpoint of hospitalization and all-cause mortality in patients with HF. Trial registration: https://www.trialregister.nl/trial/7268


Background
Heart failure (HF) is among the leading causes of morbidity and mortality worldwide [1]. Early recognition and prompt treatment of heart failure are crucial for the prognosis. Although HF is primarily a clinical diagnosis, N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a valuable diagnostic marker of HF given the fact that symptoms can be aspecific [2]. Patients with normal NT-proBNP levels are unlikely to have HF, contrary to patients with elevated levels who need further cardiac evaluation.
Echocardiography is the modality of choice to establish the diagnosis of HF. The classification is based primarily on measurement of left ventricular ejection fraction (LVEF) into HF with reduced (≤ 40%), mildly reduced (41-49%), or preserved (≥ 50%) ejection fraction [3]. Currently, the evaluation of HF is mainly focused on the left ventricle (LV). This is remarkable since left atrial (LA) Open Access *Correspondence: Sjoerd.bouwmeester@catharinaziekenhuis.nl † Sjoerd Bouwmeester and Jonna A. van der Stam have contributed equally to this work 1 Department of Cardiology, Catharina Hospital Eindhoven, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands Full list of author information is available at the end of the article volume and function has a pathophysiological significance in different types of HF [4,5]. Accumulating evidence suggests an added value of measuring the left atrial reservoir strain (LAS r ) by speckle-tracking echocardiography for both diagnosis and prognosis of HF [6,7]. Previous studies showed that LAS r is around 40% in healthy controls [8] and that it is impaired in HF patients [6,7]. Additionally, LAS r can be used as a prognostic marker similar to NT-proBNP [9].
The aim of the study is to investigate the correlation between LAS r and NT-proBNP and its prognostic value in an outpatient population with HF with regards to the composite endpoint of HF hospitalization and all-cause mortality within 1 year.

Study design
The present study was performed as part of the Heart Failure Classification (HaFaC) project (https:// www. trial regis ter. nl/ trial/ 7268). This prospective, non-randomized, observational, single-center study was designed to develop a HF classification based on objective measurement data. The local ethics committee and the Institutional Review Board approved the study (Medical Research Ethics Committees United study number NL60579.100.17) and all subjects gave written informed consent. The primary outcome was a composite of allcause mortality or hospitalization for heart failure.

Population
From December 2017 to September 2019, patients referred to the Echocardiography Lab with HF based on the ESC guidelines [10] were prospectively included in the study. To be included, patients needed to be ≥ 18 years old and able to provide written informed consent. Exclusion criteria were: recent cardiothoracic surgery (≤ 90 days) or pregnancy. Patients were also excluded for further analysis in case of inadequate acoustic LA window on echocardiography (> 2 non-visible LA segments), and severe renal failure (glomerular filtration rate ≤ 30 mL/min, calculated by the CKD-EPI formula). Also patients with atrial fibrillation were excluded, because atrial fibrillation on its own induces LA remodeling and influences LAS r . All patient data was entered into a prospective database, including demographical, clinical and echocardiographic variables, medications and laboratory biomarkers.

Echocardiographic evaluation
All patients underwent a comprehensive transthoracic echocardiographic examination using commercially available equipment (Philips iE33 or Philips EPIQ, Andover, MA, USA). Examinations were performed by 2 experienced and EACVI certified cardiac sonographers (SB or PH), blinded to other research data. Echocardiogram was stored as Digital Imaging and Communications in Medicine (DICOM) file on a secured server and analysed off-line using commercially available software (QLAB 13, Philips Healthcare, Eindhoven, the Netherlands). Standard 2D-and Doppler-echocardiographic measurements were performed following ASE/EACVI guidelines [11]. LVEF was calculated using the modified biplane Simpson's rule and maximum LA volume was calculated by the biplane method of disks at endsystole and indexed to body surface area (LAVI). The following parameters were used to determine diastolic dysfunction; average E/e' > 14, septal e' velocity < 7 cm/s or lateral e' velocity < 10 cm/s, tricuspid regurgitation velocity > 2.8 m/s, LAVI > 34 ml/m2, pulmonary vein S/D ratio < 1, mitral inflow velocities and ratio according to the published guidelines [11].
Speckle tracking echocardiography of the LA is a relatively new echocardiographic method. With dedicated software an unique pattern of speckles is identified within the LA wall and these speckles are tracked on frame-by-frame base throughout the cardiac cycle. The measured change in distance between the different speckles is used to calculate LA deformation. LA reservoir strain is a prognostic biomarker, which has been evaluated for patients with HF. Commercially available software (QLAB 13, Philips Healthcare, Eindhoven, the Netherlands) was used to measure LAS r on non-foreshortened apical four-and two-chamber views of the LA with a frame rate of 60-80 frames per seconds. The LA endocardial border was automatically drawn followed by manual adjustment if required. The reference point for LA strain analysis was taken at the onset of the QRScomplex (R-R gating) ( Fig. 1) [12].

Biomaker analysis
Blood samples were collected and analyzed directly after the echocardiographic examination while the patient was still in a supine position. Levels of NT-proBNP were determined at the department of Clinical Chemistry (Elecsys pro BNP II assay, Roche Diagnostics, Mannheim, DE) [13].

Follow-up
Patients were followed up at our outpatient clinic on a regular base by both clinical visits and telephone calls. All-cause mortality was recorded by consulting the Dutch civil registry. Information on HF hospitalization during the 1-year follow-up period was obtained from a systematic review of all hospital admissions performed by an independent reviewer unaware of clinical and echocardiographic data.

Statistical analysis
Three groups were defined: HF with preserved ejection fraction (HFpEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with reduced ejection fraction (HFrEF) [10]. For continuous variables, normality of distribution was assessed with the Shapiro-Wilk's test. Normal and skewed continuous variables are presented as means with standard deviation (SD) and medians with interquartile range [IQR], respectively. Statistical comparisons of the three HF subgroups were made using one way ANOVA for normally distributed data or an Kruskal Wallis test for non-normally distributed data. Categorical variables were expressed as proportions and compared using a chi-squared test, or Fishers exact test when the number of positive cases in at least one of the heart failure categories is less than five. Multiple pairwise-comparison between subgroups was performed using Tukey Honest Significant Differences method for

Correlation between biomarkers and LAS r
The study population showed a moderate inverse correlation between NT-proBNP and LAS r (r = − 0.55 p < 0.01), which improved after 10 log-transformation of NT-proBNP (r = − 0.75, p < 0.01) (Fig. 3). For the HF subgroups, no significant differences were found between the degree of correlation between 10 log-transformed NT-proBNP and LAS r .

Correlation between conventional echocardiographic diastolic parameters and LAS r
Both deceleration time of early mitral inflow (E) and early diastolic mitral annular velocity (e') had a weak correlation with LAS r (r = 0.35 and r = 0.24, respectively). E/A and E/e' ratio had a moderate inverse correlation with LAS r (r = − 0.44 and r = − 0.42, respectively).

Follow-up
Twenty-three patients (13%) reached the composite endpoint of all-cause mortality and heart failure hospitalization (Table 1).

Prognostic value of LAS r and biomarkers
Results of receiver operating characteristic (ROC) analysis for all predictors of the endpoint are shown in Fig. 4 and Table 3. NT-proBNP showed the highest area under the ROC curve (AUC 0.83) to predict the primary endpoint of death or heart failure hospitalization up to 12 months of follow-up. As for echocardiographic parameters, LAS r outperformed LVEF with a AUCvalue of 0.79. The AUC of LAS r differed significantly from LAVI and LVEDV (p < 0.01 and p = 0.03), however not from LVEF and NT-proBNP (p = 0.10 and p = 0.25).

Discussion
The key findings of the present study are as follows. First, LAS r is a strong echocardiographic predictor of the composite endpoint of HF hospitalization and all-cause mortality. Compared to NT-proBNP, LAS r predicts the endpoint with a comparable specificity (83% vs. 84%), however with a lower sensitivity (70% vs. 61%). Also, LAS r correlates strongly with 10 log-transformed NT-proBNP levels. LAS r has enhanced prognostic value beyond conventional echocardiographic measures to discriminate which heart failure patients are at greater risk for hospital admission or death. For HF subgroups, Carluccio et al. [15] and Freed et al. [16] showed that assessment of LAS r by speckle-tracking strain echocardiography had powerful prognostication in patients with HFrEF and HFpEF, respectively.
Although limited in number, previous studies that investigated the correlation between NT-proBNP and LAS r , are in line with our results. Al Saikhan [7] demonstrated a modest inverse correlation in patients with both HFpEF (r = − 0.57) and HFmrEF (r = − 0.53). Another study showed that LAS r had moderate inverse correlation with NT-proBNP (r = − 0.42) [14]. In both studies, the correlation between LAS r and a log-transformation of NT-proBNP levels was not reported, although it has Table 3 Receiver operating characteristic to predict adverse events been shown that plasma concentrations of NT-proBNP follow a log-normal distribution in patients with HF [13]. Prastaro [5] evaluated the relationship between NT-proBNP and LA function in patient with HFrEF. In their study, LA function was based on measuring fractional active and total emptying from M-and B-mode images and showed a significant correlation between NT-proBNP and LA function [5].

LA reservoir strain and elevated LV filling pressure
Assessment of LV filling pressure has important diagnostic and prognostic implications in patients with HF [10,11]. Although right-sided cardiac catheterization is the gold standard to determine LV filling pressure, it is unattractive for routine clinical use given its invasiveness. In the continuing search for non-invasive markers to estimate LV filling pressure, NT-proBNP provides a reliable estimation, especially for left ventricular enddiastolic pressure (LVEDP) [17]. The prognostic value of NT-proBNP is well established [9,10] and the results of our study are in line with previous reports. The LA, on the other hand, is more and more acknowledged as key player in the pathophysiology of systolic and diastolic HF [18]. Indeed, elevated LV filling pressure results in pressure overload that induces LA failure characterized by dilation and decrease in reservoir function. Wakami [19] showed that an increase in LVEDP is associated with a decrease in LAS r . Moreover, LAS r can accurately categorize patients based on a normal or elevated LV filling pressures [14,20].

LA reservoir strain and heart failure
In HFpEF a fortiori, elevated filling pressures are the main physiologic consequence of the diastolic dysfunction [21]. Current guidelines [11] use various echocardiographic parameters for determination of diastolic dysfunction. LAS r provides potentially clinical relevance in the detection of LV diastolic dysfunction, because LAS r detects subtle dysfunction, even before the LA begins to enlarge [22]. LAS r decreases in a linear fashion as LV diastolic dysfunction progresses [23]. In line with this, the latest EACVI document [24] encourages the use of LA strain in the assessment of diastolic function and filling pressures in HFpEF, however LAS r should not be used in patients with atrial fibrillation [25]. We previously showed a relationship between increased coronary microvascular resistance and reduced LAS r , that seemed to precede conventional measures of LV diastolic dysfunction [26]. Moreover, LAS r is not only influenced by diastolic, but also by systolic LV function. As LA expansion is also determined by the base-to-apex displacement during LV systolic contraction [27], any condition that influences LV myocardial function is expected to influence LAS r . Thus, LAS r correlates with both LV filling pressures and systolic performance.

Clinical implications
The LA seems to have a central role in HF. LA function can be easily studied using speckle-tracking strain echocardiography. The LA strain measurements should be included in the standard evaluation of outpatients with heart failure, because it can stratify their risk for hospital admission and death more reliable than LVEF. Further research is need if a closer follow-up of these patients will reduce their morbidity and mortality.

Study limitations
Although the current study is based on a real-world, prospective, observational data of an outpatient HF population referred to the echocardiography lab, the subgroups of different HF types were relatively small. Second, the number of events was too small to perform a multivariate Cox regression analysis. A logistic regression with NT-proBNP and echocardiographic parameters did not result in an improvement in AUC. However, follow-up research with a larger population and more events is needed to draw conclusions on the AUC of combined laboratory and echocardiographic parameters. Third, the length of follow-up in the current study was limited to 1 year, so we were unable to determine the long-term prognostic value of LAS r . Fourth, in this prospective study a combined endpoint of HF hospitalization and all-cause mortality has been chosen. Cardiovascular death might have been a stronger endpoint. However, the exact cause of death was not known in all of our HF patients. Finally, in 7% of the study population, LAS r could not be analyzed due to poor image quality.

Conclusions
LAS r is a strong echocardiographic predictor of the composite endpoint of HF hospitalization and mortality. LAS r is inversely correlated with NT-proBNP and predicts the endpoint with a comparable specificity.