Prognostic impact of left atrial function in heart failure with preserved ejection fraction in sinus rhythm vs. persistent atrial fibrillation

Study design

This study was performed at the Division of Cardiology at the Medical University of Vienna, a tertiary care centre with a high-volume cardiac catheterization laboratory and heart failure outpatient clinic. It was approved by its local ethical committee (EK No. 796/2010). From December 2010 to March 2017, consecutive patients were screened for HFpEF. All study participants gave written informed consent and were enrolled in a prospective observational fashion.

Clinical definitions

The diagnosis of HFpEF was based on guideline recommendation,¹⁶ including (1) signs or symptoms of heart failure, (2) preserved systolic LV ejection fraction (EF) (EF ≥ 50%), (3) elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (>220 pg/mL), and (4) signs of diastolic dysfunction or structural changes such as LA enlargement or LV hypertrophy. In addition, we invasively confirmed elevated pulmonary artery wedge pressure to confirm the diagnosis of HFpEF. All patients underwent invasive coronary angiography. Reasons for exclusion were significant coronary artery disease on coronary angiography, significant valvular disease except tricuspid regurgitation, congenital heart disease, or signs of myocardial storage disease like amyloidosis. Screening for amyloidosis was performed according to current recommendations.¹⁷

Assessment techniques

Outcome measures

Study participants were followed by telephone calls and 6 months ambulatory visits including ECG. Primary outcome measure was a composite endpoint of hospitalization for heart failure and death from cardiovascular causes. Events were ascertained by follow-up visits and phone calls and adjudicated by an internal adjudication committee, who were blinded to patient characteristics as well as imaging and haemodynamic data.

Statistical analysis

Continuous variables are expressed as mean ± standard deviation or as median and interquartile ranges. Categorical variables are presented as numbers and per cent. Continuous variables were compared using the Mann–Whitney U-test, and for dichotomous variables, the χ² test was applied. Spearman (ρ) test was used to find factors correlated with LA phasic function and volumetric analyses.

Parameters were divided into clinical, general, and specific LA CMR imaging and invasive haemodynamic categories. To define factors associated with AF, univariate logistic regression analysis was calculated for each parameter (Table 1).

To assess associations with event-free survival, separate univariate Cox regression models were performed for all specific LA CMR parameters for patients in SR and in AF (Table 3). Adjusted hazard ratios (adj. HR) per 1-SD decline in conduit, booster pump, and total LA-EF or 1-SD increase in maximum and minimum LAVi were calculated. Adjustment was performed for age, 6MWD, NT-proBNP, and RV EF (Figure 1).

Kaplan–Meier plots (log-rank test) were applied to verify the time-dependent discriminative power of maximum and minimum LAVi, conduit, booster pump, and total LA-EF on cardiovascular outcome (Figures 1, 2, and 3).

In an exploratory step, we performed restricted cubic splines (three knots) to assess the association between LA-EF and the composite endpoint and identify a potential cut-off value indicating higher risk (Figure 4). In addition, receiver operating characteristic analysis and the Youden Index were used to report a cut-off value in our cohort with best discriminative power for event prediction.

Statistical analyses were performed using dedicated software (IBM SPSS Version 21, SPSS Inc, Chicago, IL) and Stata 15.1 (StataCorp, College Station, TX) with significance level set to P < 0.05 for all tests unless stated otherwise.

Study population

Between December 2010 and November 2017, a total 343 HFpEF patients were screened for enrolment. Fifty patients were excluded because of significant coronary artery disease (n = 18), NT-proBNP < 220 pg/mL (n = 16), cardiac amyloidosis (n = 15), and chronic thromboembolic pulmonary hypertension (n = 1). One hundred and five patients did not undergo CMR either due to contraindications (n = 46) or refusal (n = 52), and n = 7 (in AF during CMR examination) were excluded due to insufficient CMR image quality for LA function analysis. CMR analysis time was not significantly prolonged in AF patients.

The final study cohort comprised 188 patients. Table 1 displays clinical and CMR baseline characteristics stratified by ECG rhythm. Ninety-six patients (51%) were in SR and 92 (49%) in AF at the time of CMR. All AF patients had persistent AF. Thirty (31%) patients in SR at the time of CMR had a history of paroxysmal AF but did not differ from SR patients according to baseline characteristics (Supporting Information, Table S1). Patients in AF were older (P = 0.017), had a higher heart rate (P = 0.014), a shorter 6MWD (P = 0.040), and were in worse New York Heart Association functional class (P = 0.003). Furthermore, they had higher serum levels of NT-proBNP and gamma-glutamyl-transferase (each P < 0.001, respectively).

On CMR, patients with AF had markedly pronounced bi-atrial and RV dilatation and decreased bi-ventricular EF as compared with patients with SR (each P < 0.001 respectively, except for RV end-diastolic-volume P = 0.035). In addition, patients with AF presented with higher ECV on CMR (P < 0.001). No positive late gadolinium enhancement was found in any patient.

Left atrial volume and function in sinus rhythm vs. atrial fibrillation

All phasic volume parameters were significantly increased, and in contrast, total LA-EF significantly impaired in AF patients when compared with those in SR (Table 1; P < 0.001 for all).

Notably, among SR patients with and without a history of paroxysmal AF, no significant differences were observed (P > 0.05 for all; Table S1).

Left atrial function in correlation to functional capacity and backward and forward coupling

Table 2 summarizes the association of phasic LA function and markers of exercise capacity, LV diastolic function, and pulmonary vascular function. By correlation analysis, in patients with SR, LA conduit function (but not booster pump function) was significantly related with 6MWD (ρ = 0.24, P = 0.032). In addition, LA conduit function was significantly correlated with systolic pulmonary artery pressure (sPAP) (ρ = −0.22, P = 0.049) and pulmonary vascular resistance (ρ = −0.40, P = 0.001) as markers for backward coupling to the pulmonary vasculature. However, LA volumetric and functional parameters were not significantly correlated with LV EF (as evaluated by CMR) (Table 2). Furthermore, total LA-EF showed no significant correlation with LV global longitudinal strain in SR as well as in AF (ρ = −0.01, P = 0.975 and ρ = −0.11, P = 0.362, respectively). LA conduit function was not associated with NT-proBNP levels and LV end-diastolic pressure (ρ = −0.11, P = 0.319 and ρ = −0.02, P = 0.910, respectively). In contrast, LA booster pump EF, LA total EF, and all phasic LAVi were significantly correlated with NT-proBNP (each P < 0.001, respectively). In AF patients, LA functional parameters showed no significant correlations with 6MWD, sPAP, and pulmonary vascular resistance (P > 0.05 for all).

Left atrial function and cardiovascular outcome

Patients were followed for 31 (9–57) months. Sixty-five (35%) patients reached the combined endpoint defined as hospitalization for heart failure (n = 60) or cardiovascular death (n = 5). Patients with persistent AF were at significantly higher risk to experience the composite endpoint as compared with patients in SR [HR 3.02, 95% confidence interval (CI) 1.77–5.16, log-rank, P < 0.001]. Table 3 summarizes details of the univariable Cox regression results.

In patients with SR, several LA volumetric and functional parameters were related with outcome in the univariable regression analysis. In contrast, in patients with persistent AF, no LA parameter was related with outcome (Table 3 & Figures 2 and 3). However, these patients carried a similarly dismal prognosis when compared with patients in SR with impaired LA-EF (log-rank, P = 0.340) (Figure 1).

Figure 1 displays the association of LA volumetric and functional parameters with outcome adjusted for established risk factors, including age, 6MWD, NT-proBNP, and RV EF in SR vs. persistent AF. In SR, LA-EF is independently related with outcome (adj. HR 1.60, 95% CI 1.14–2.34, P = 0.006). This effect seems to be mainly driven by LA conduit EF (adj. HR 2.03, 95% CI 1.17–3.51, P = 0.012) (Figure 3). Furthermore, also minimum LAVi is independently related with outcome (adj. HR 1.52, 95% CI 1.11–2.08, P = 0.012). In patients in persistent AF, no LA parameter was related with outcome after adjustment for established risk factors (Figure 1).

In receiver operating characteristic analysis and Youden's J statistics demonstrated that an LA-EF cut-off of <40% carried a sensitivity of 90% and specificity of 65% (area under the curve 0.77; 95% CI 0.65–0.90) to predict an adverse outcome. This cut-off was further confirmed by visual assessment in a restricted cubic spline model demonstrating a stark increase in risk for events when LA-EF is lower than 40% (Figure 4).

Prognostic value of left atrial volume and function

Left atrial enlargement has long been recognized as key feature in patients with HFpEF and reflects increased filling pressures due to diastolic dysfunction. Maximum LAVi is an established risk factor for the prediction of cardiovascular events.^{8, 21} More recent studies suggest that LA-EF and minimum LAVi are even more closely related with prognosis in the elderly and in HFpEF patients as compared with maximum LAVi.^{6, 8, 22, 23} These findings are in line with our results where minimum LAVi and total LA-EF outperformed maximum LAVi in predicting cardiovascular events (Table 3 & Figure 3), even after adjustment for established risk factors in HFpEF such as age, 6MWD, NT-proBNP, and RV EF (Figure 1).^{3, 18, 24, 25}

Left atrial function in sinus rhythm and correlation to functional capacity and pulmonary vasculature

In SR, total LA-EF is put together by the passive conduit EF, which starts just after mitral valve opening and active booster pump EF, which represents active LA contraction.

In contrast to LA booster pump and total EF, LA conduit function did not show any association with NT-proBNP. Considering its close correlation with sPAP and pulmonary vascular resistance, it can be assumed that parameters of LA conduit function are rather reflecting pulmonary vascular than cardiac performance.²⁸

Specific considerations concerning heart failure with preserved ejection fraction with persistent arterial fibrillation

Data regarding LA function in the context of AF in patients with HFpEF are limited.¹³ However, this is important as a substantial fraction of these patients present with AF.

Almost 65% of our study participants had a history of AF (16% paroxysmal & 49% persistent AF), which is in line with previous reports.^{12, 29} No difference regarding LA parameters was shown between patients with a history of paroxysmal AF and SR (Table S1), whereas patients in persistent AF presented with significantly increased LA volumes and relevant functional impairment (Table 1). LA parameters in AF patients were not associated with cardiovascular events, not even in the univariate analysis (Table 3 & Figures 2 and 3). This most likely was related to the fact that AF patients were at advanced stages of the disease, were older, and presented with shorter 6MWD, impaired RV performance, and higher LV ECV (Table 1).^{3, 18, 25, 30} Apparently, at this stage of disease, LA performance had lost its prognostic impact.

AF, and in particular persistent AF, is an established independent marker for adverse outcome in HFpEF.^{12, 29} Our data implicate that further risk stratification by evaluation of LA size and function is not expedient in this patient population. On the other hand, HFpEF patients in SR with an LA-EF < 40% have a similar risk for adverse outcome compared with HFpEF patients in persistent AF.

Limitations

This was a single-centre study; thus, a centre-specific bias cannot be ruled out although single-centre studies have several advantages such as homogenous patient selection, continuous workflow, and constant follow-up. Patients in AF during CMR study were deliberately not excluded from the trial as the proportion of HFpEF patients suffering from AF is up to 60%.^{29, 12} Furthermore, volumetric assessment of LA function in patients with AF during CMR image acquisition is well validated.¹⁵

However, it remains a limitation that LA volumetric assessment was not performed four-dimensional.

Also, image quality on CMR and scan times may be influenced in case of substantial arrhythmias. Although CMR studies with under average image quality were excluded from the analysis and LA volumetric analyses were performed as an average of three biplane measurements (equals six measurements), measuring errors cannot be fully excluded. As continuous ECG monitoring, for example, by implantable loop recorders was not performed in every patient, asymptomatic AF episodes may have been missed and real life burden of AF episodes might be higher. The cross-sectional observational study design limits conclusions about cause–effect relationships.

Clinical implications

For HFpEF patients in SR, assessment of LA-EF is superior to static LA volumetric measurements in predicting adverse events. Our data as well as several other studies support its major superiority over still widely used maximal LA expansion⁸ for defining HFpEF patients at risk to experience future cardiovascular events. Our results suggest an LA-EF value of <40% (in HFpEF SR) as the best predictive cut-off for adverse cardiovascular outcome. However, large-scale future studies are warranted to confirm this value.

Further studies on treatment of the underlying atrial myopathy in early stages of HFpEF including pharmacological intervention³¹ or AF ablation³² are warranted to possibly prevent further deterioration of LA function accompanied by the onset of permanent AF and pericardial restraint.¹³