Exercise Left Atrial Compliance: One More Tool in the Heart Failure with Preserved Ejection Fraction Assistance Toolbox?

This article refers to ‘Diagnostic value of reduced left atrial compliance during ergometry exercise in heart failure with preserved ejection fraction’ by T. Harada et al., published in this issue on pages 1293–1303. Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases; however, the exact clinical diagnosis of HFpEF remains challenging. According to the 2021 European Society of Cardiology guidelines, exercise invasive haemodynamic cardiac catheterization remains the gold standard to unequivocally confirm the diagnosis of HFpEF for those with inconclusive results from diagnostic criteria.1 Typical haemodynamic presentations in HFpEF patients may include elevations in left ventricular end-diastolic pressure (LVEDP), pulmonary capillary wedge pressure (PCWP), and pulmonary artery pressure, which occur in parallel to each other. Provoked haemodynamics during exercise is crucial for patients with HFpEF, as some patients with HFpEF may show normal PCWP at rest under scenarios of decongestive or euvolaemic status (masked) and manifest a steep rise of PCWP during exercise from increased venous return into a more stiff left ventricle.2 In this case, abnormal haemodynamic responses during exercise, yet maintained within normal range at rest, reflects impaired diastolic functional reserve in HFpEF, and may lead to limited exercise capacity presenting with exertional dyspnoea and effort intolerance (Figure 1).3 This emphasizes the role of exercise stress test and exercise haemodynamic data. Traditional echocardiography as a non-invasive imaging diagnostic modality has been widely used to assess several diastolic parameters as alternatives to invasive measures. These may include mitral inflow velocities, early diastolic mitral annular relaxation velocity (e'), and the ratio of early mitral inflow velocity divided by early diastolic mitral annular velocity (E/e').4 On the other hand, echocardiography further enables characterization of several morphological features tightly linked to HFpEF pathophysiology, including left atrial (LA) size and patterns of left ventricular (LV) remodelling5 (Figure 1). Recently, advanced echocardiographic measures enable early identification of diastolic dysfunction and provide multiple measures (such as cardiac deformational strains and strain rates) closely related to each of the aspects of LV diastolic function both at rest and during exercise.5 More importantly, some of these non-invasive measures have been extensively validated against invasive gold standard estimates.6 Among these estimates, LA remodelling and mechanics have been shown to play a central role in HFpEF pathophysiology. Without a doubt, LA function plays a pivotal role in the pathophysiology of HFpEF. The importance of LA functional assessment is underscored by the fact that anatomic left atrium is directly influenced by LV filling pressure. LA structural and functional adaptation provides an important compensatory mechanism to preserve cardiac output in the early stages of LV diastolic dysfunction and is described based on different phases: during LV systole, blood flows from the pulmonary veins into the left atrium (reservoir phase); during early diastole and diastasis, the left atrium serves as a passive conduit (conduit phase); during late LV diastole, active LA contraction further boost to augment LV filling (booster phase). These phasic LA mechanics can be readily delineated and objectively quantified using speckle tracking echocardiography. Normal LA reserve allows the increase in LA volume during the reservoir phase to maintain a normal filling pressure. However, reduced LA compliance as a functionally limited reservoir chamber (less distensible) to receive venous return during exercise may lead to marked elevation of LA pressure and backward upstream pulmonary artery pressure compared to normal LA condition. This may result in subsequent LA failure and eventually catalyzes the transition from LV diastolic dysfunction to HFpEF development.7 Venkateshvaran et al.8 have previously reported that adding LA reservoir strain to the diagnostic algorithm of diastolic dysfunction improves the accuracy in detecting elevated PCWP measured invasively. It has also been shown that adding LA strain can better stratify the severity of diastolic dysfunction.9, 10 Telles et al.11 found that LA reservoir and contractile strain were independent predictors and better characterize exercise PCWP than LA volume index (LAVi) among HFpEF patients verified using invasive measure. It is also shown that LA reservoir strain during leg lifts, which increase the preload of the left atrium, can detect concealed abnormalities in LV diastolic dysfunction; moreover, models with addition of LA reservoir strain at rest and at leg lifts provided incremental value over models with conventional echocardiographic parameters (e.g. E/e') in differentiating HFpEF patients versus the control group.12 Although some provocative manoeuvres, such as leg lift, could also help diagnose HFpEF, they do not replicate the dyspnoea on exertion that patients experience and are less physiologically relevant, highlighting the importance of an exercise test in HFpEF diagnosis. These studies provide the opportunity to reinforce the understanding of a key concept that LA function during exercise may reflect the true functional status of patients with HFpEF. According to the HFA-PEFF score, LAVi along with other echo-based parameters (including E/e', LV mass index, relative wall thickness) are essential and integral components in the diagnosis of HFpEF.13 In the current issue of the Journal, Harada et al.14 determined LA compliance with the ratio of LA reservoir strain to E/e'. They successfully confirmed that LA compliance during exercise demonstrated superior diagnostic ability to exercise E/e' ratio, with incremental diagnostic value over the resting LA compliance in two separate cohorts. An appreciable sample size (n = 602) patients underwent exercise stress echocardiography. Harada et al. demonstrated that resting LA compliance (area under the curve [AUC]: 0.81 [0.77–0.85]) outperformed resting E/e' ratio (AUC 0.75 [0.70–0.79]). The DeLong test utilized to assess the significance of AUC difference revealed a highly significant p-value (DeLong test, p = 0.001). Furthermore, the diagnostic performance of LA compliance was significantly improved during exercise (DeLong test, p = 0.0008 vs. rest) with the largest AUC (0.87 [0.83–0.90], p < 0.0001). The diagnostic yield of LA compliance also appears to be superior to that of the E/e' ratio during exercise (AUC: 0.87 vs. 0.81, respectively) (DeLong test, p = 0.005). The authors furthered verified the finding in 67 patients (49 patients with HFpEF and 18 patients with non-cardiac dyspnoea) who underwent clinically indicated exercise right heart catheterization after exercise stress echocardiography. Notably, the authors reported that exercise LA compliance may have the best ability to discriminate HFpEF from non-cardiac dyspnoea with an incremental diagnostic value over the resting information. The authors proposed the utilization of exercise LA compliance for the first time as a diagnostic tool in HFpEF. These findings are important and suggest that incorporating LA functional assessment, rather than LAVi alone, is clinically feasible and probably provides incremental value to aid in HFpEF diagnosis during exercise, as structural and functional LA remodelling may serve as an indicator representing the chronicity of exposure to abnormal LV filling pressure. It is not surprising that integrating information of LA reservoir strain and LVEDP during exercise (as LA compliance) would likely serve as a better surrogate marker compared with each of them alone. Findings from this study also shed light on the possibility of refining HFpEF diagnostic algorithm in the future by incorporating the concept of ‘stiff LA syndrome’ featured by reduced LA compliance at rest and particularly during exercise stress condition (Figure 1). So what about the usefulness and pathophysiological significance of LA compliance in HFpEF diagnosis? In 1992, Hoit and Walsh15 conducted an in vivo experimental animal study to evaluate LA distensibility and compliance by modulating using pressure–volume relationships. Kurt et al.7 proposed using E/e' to LA reservoir strain ratio as a non-invasive parameter to differentiate patients with HFpEF and those with diastolic dysfunction without heart failure. A recent study also showed that LA reservoir strain discriminated HFpEF from non-cardiac dyspnoea and outperformed LV deformation; adding LA compliance (or stiffness, LA reservoir stain divided by E/e') further improved the diagnostic performance as compared with LA strain alone.16 In other words, LA reservoir strain and LA compliance measurements have been shown to provide additional value as compared to traditional parameters assessing degree of LA remodelling, for example, LAVi. Future incorporation of LA reservoir strain or LA compliance in the algorithm of HFpEF diagnosis could be considered. While the findings from Harada et al.14 are inspiring for exploring the new imaging modality and may encourage the utilization of non-invasive stress test for HFpEF diagnosis, the clinical generalizability for such a novel tool remains to be determined. Second, there might exist a proportion of HFpEF patients presenting with exercise intolerance yet unable to complete a stress test from limited physical strength (such as sarcopenic patients). Third, can these non-invasive measures, when multiple parameters are combined all together, completely replace the current use of exercise invasive catheterization as gold standard (PCWP or LV filling pressure)? Finally, there might be some distinct features simply comparing the patients with unexplained dyspnoea referred from outpatient clinics and those hospitalized for acute heart failure. These questions are important and may need further research. Conflict of interest: none declared.