Left atrial stiffness by echo: rationale, feasibility, and future directions

This editorial refers to ‘Prognostic value of left atrial stiffness index in adults with repaired coarctation of aorta’, by O. Abozied et al., https://doi.org/10.1093/ehjci/jeaf330. Although heart failure with preserved ejection fraction (HFpEF), previously known as diastolic heart failure, has been recognized as a clinical entity for several decades, only recently has evidence-based, disease-modifying therapy become available. A breakthrough occurred with the demonstration that sodium–glucose cotransporter-2 inhibitors reduce morbidity and mortality in HFpEF.1,2 In these pivotal trials, the only imaging parameters included beyond left ventricular ejection fraction (LV EF) were left atrial (LA) size and LV hypertrophy as markers of structural heart disease. As illustrated in Figure 1A, the LA is enlarged in most HFpEF patients, but a substantial fraction has normal LA size. Potentially, more refined HFpEF diagnostics could have improved patient selection and thus enhanced the positive responses beyond what was achieved in the trials referred to above. Since the initiation of those studies, LA strain has emerged as a powerful heart failure biomarker.6 Unlike LA volume—which reflects chronic exposure to elevated pressure—LA strain reflects both instant and chronic effects of elevated LA pressure and provides a measure of LA reservoir and pump function. Panel A, adapted from M. R. Zile et al.3 (with permission). Panel B, light microscopy image (Masson’s trichrome stain) of atrial tissue with myocyte loss and expansion of interstitial fibrous tissue. Adapted from A. Goette et al.4 (with permission). Panel C is a schematic illustration of method to calculate LA chamber stiffness. Panels D–F present a head-to-head comparison of LA volume index, E/e′ and LA reservoir strain as imaging markers of LV filling pressure in patients evaluated for suspected heart failure. Data are replotted with permission from a study of K. Inoue, F. H. Khan et al.5. In addition to macroscopic LA remodelling reflected in increased LA volume, longstanding elevation of LA pressure also leads to microscopic atrial remodelling, which is a feature of LA myopathy. As illustrated in Figure 1B this includes fibrosis and extracellular matrix expansion, leading to a stiffer atrium and therefore reduced LA reservoir function. Currently, no imaging modality is available to directly assess LA tissue structure; even cardiac magnetic resonance imaging does not provide the diagnostic information required for this purpose.7 An alternative approach is to assess LA chamber stiffness, as illustrated in Figure 1C, defined as the ratio of the change in LA pressure to the change in LA volume. However, no clinically established marker of LA stiffness is currently available. Therefore, LA stiffness is a missing parameter in heart failure diagnostics, even though a LA stiffness index has been proposed, calculated as the ratio of E/e′ to LA reservoir strain.8,9 In this issue, an article by A. Egbe et al.10 evaluates this LA stiffness index as marker of disease severity and prognosis in patients with aortic coarctation (CoA). CoA explores whether LA stiffness index, defined as the ratio of septal E/e′ to LA reservoir strain, has prognostic value. As disease severity indices they used right ventricular to pulmonary artery coupling, NT-proBNP, and predicted peak VO2. A subgroup analysis of patients who underwent right heart catheterization (n = 114) within 12 months of baseline echocardiography showed good correlation between pulmonary capillary wedge pressure (PCWP) and LA stiffness index (r = 0.79). The cohort was divided into high (>0.28) and low (≤0.28) LA stiffness index groups. Patients with high LA stiffness index were associated with higher rate of heart failure hospitalization and higher all-cause mortality (Hazard ratio 3.17 and 2.81, respectively). The LA stiffness index also correlated well with the disease severity indices. The LA stiffness index had prognostic performance that was superior to LA reservoir strain and septal E/e′. The study concludes that LA stiffness index improves prognostication in adults with CoA and can potentially be used to guide timing of intervention or monitor response to therapy. Strengths of the study are the large size of the population and the validation of the LA stiffness index against PCWP, which showed good correlation between the two variables. The study is limited by its retrospective design, and it was performed at a single centre. When introducing novel parameters in cardiac diagnostics, it is essential to identify a sound mechanistic rationale for their use. In this context, one must ask why the proposed LA stiffness index should be considered superior to measuring E/e′ and LA strain separately and using them in combination as recommended in current guidelines. Considering the wide scatter shown in Figure 1E, it is evident that E/e′ is not an accurate indicator of LA pressure, even though elevated E/e′ values are generally associated with increased LA pressure. Furthermore, it is not the absolute LA pressure but the change in LA pressure that constitutes the numerator in the calculation of LA stiffness, as illustrated in Figure 1C. Therefore, the LA stiffness index applied in the study of Alexander Egbe et al.10 does not measure LA stiffness in corrects physical terms. The rationale behind using E/e′ as marker of LA pressure is that mitral E reflects the transmitral pressure gradient, and e′ as parameter of LV relaxation reflects minimum LV pressure. Therefore, when e′ is subnormal, there is typically elevated minimum LV pressure, and a high transmitral pressure gradient on top of elevated minimum LV pressure, means high LA pressure. More recently LA reservoir strain was introduced as a stronger marker of LA pressure than LA volume index and E/e′. Figure 1E and F illustrate the relatively strong association between both E/e′ and LA reservoir strain and LA pressure measured indirectly as PCWP or pre-A LV pressure. The observed correlation between the LA stiffness index and PCWP in the study by Egbe et al.10 may be driven by the associations of E/e′ and LA reservoir strain with PCWP, rather than a direct association with LA stiffness. Nevertheless, a stiffer atrium would be expected to exhibit higher LA pressure and reduced reservoir strain, providing a physiological rationale for the use of the LA stiffness index as a surrogate measure of atrial stiffness. The diagnostic utility of LA stiffness index needs validation in different populations and its cut-offs for normality should be defined. It would also be interesting to see if change in LA volume using 3D echocardiography may provide a more optimal measure of dimensional change than LA reservoir strain when calculating the LA stiffness index. Future studies should investigate if echocardiographic estimates of change in LA pressure may be combined with LA strain or volume change to provide a more appropriate stiffness index. In conclusion, the study by Egbe et al.10 in CoA operated patients is interesting as it focuses on LA stiffness, which is a missing parameter in heart failure diagnostics. The proposed LA stiffness index incorporates E/e′ as a marker of mean LA pressure and LA reservoir strain as a surrogate of atrial dimension. Although these are not the fundamental parameters required to directly quantify stiffness, the index may still have clinical value, not as a true measure of LA stiffness, but rather as an indirect surrogate. Further validation in different heart disease phenotypes is required before conclusions can be drawn regarding the clinical utility of the LA stiffness index. Otto Armin Smiseth (Conceptualization [lead], Project administration [lead], Supervision [lead], Writing—original draft [lead], Writing—review & editing [lead]), Katsuji Inoue (Data curation [equal], Formal analysis [supporting], Writing—review & editing [supporting]), and Faraz H. Khan (Data curation [supporting]; Writing—review & editing [supporting]) Not applicable to this editorial.